13-cis-Retinoic acid (I) is a compound of widespread use in cosmetics, due to its anti-acne properties.

Among the available methods for its preparation, the one disclosed in EP 0111325 comprises the Wittig reaction between a salt of formula (II)

and 5-hydroxy-4-methyl-2(5H)-furanone (III)

at temperatures ranging from −10 to −50° C. in a lower alcohol and in the presence of an alkali metal hydroxide, followed by isomerisation of the resulting mixture of 11,13-di-cis- and 13-cis-retinoic acid in the presence of a palladium, platinum or rhodium complex, the isomerisation occurring at a temperature ranging from 10 to 150° C., preferably from 40 to 65° C., more preferably from 45 to 55° C. 13-cis-retinoic acid can easily be isolated by cooling to a temperature preferably ranging from −15 to −10° C. and filtering the precipitate.
An improvement over this process is disclosed in EP 0644186 B1, which claims the preparation of (I) by reaction of salts of formula (II) and butenolide (III) in dimethylformamide as the solvent in the presence of lithium hydroxide, at a temperature ranging from −9 to +10° C., preferably from −5 to +5° C., even more preferably from −2 to +2° C. The resulting mixture of 11,13-di-cis and 13-cis-retinoic acid is subsequently isomerised, preferably by photochemical isomerisation at wavelengths from 200 to 600 nm. Even though this process allows to save energy costs, due to the fact that the Wittig reaction is carried out at a relatively high temperature, it still requires the use of dimethylformamide, whose use on industrial scale is undesirable, due to its toxicity and relatively high cost.
As a matter of fact, the whole procedure implies not only high costs but it is also cumbersome and can be only carried out in very large industrial plants.
Another process for the preparation of 13-cis-retinoic acid is disclosed in EP 959069, comprising the reaction of beta-ionone with a vinyl magnesium halide to give vinyl-beta-ionol, followed by the Wittig condensation of vinyl-beta-ionol with 4-hydroxy-3-methyl-butenolide to give a mixture of 13-cis-retinoic acid, 11-13-di-cis-retinoic acid and 11,13-di-trans-retinoic acid which is then subjected to photochemical isomerization.
The conversion of 11-cis, 13-cis-retinoic acid to 13-cis-retinoic acid is disclosed also in EP 850925. The photochemical isomerization requires of course a dedicated apparatus.
Also in this case the photochemical isomerization require the use of the irradiation technology, which, under the economical point of view, is not competitive with other technologies.
It would be therefore advantageous to provide a method for the preparation of 13-cis-retinoic acid which could allow both to save energy costs and avoid the use of toxic solvents.